Moderate-Hypofractionated Radical Radiotherapy for Early-Stage Prostate Cancer: A Propensity Score Matching Analysis Comparing Dose Fractionation Patterns

Abstract

Introduction

This study evaluates the clinical outcomes, survival benefits, and toxicities of two moderate-hypofractionated radiotherapy (MHRT) patterns, 60 Gy in 20 fractions (60 Gy/20f) and 70 Gy in 28 fractions (70 Gy/28f), in early-stage prostate cancer patients.

Methods

This retrospective study analyzed data from 187 patients diagnosed between 2014 and 2023, using propensity score matching to ensure efficacy assessment accuracy. The primary endpoints reported were overall survival (OS) and disease-free survival (DFS), calculated using Kaplan-Meier analysis. Toxicity and side effects were evaluated using Criteria for Adverse Events v5.0, focusing on the urinary and gastrointestinal (GI) systems.

Results

After matching, each of the 60 Gy and 70 Gy groups included 73 patients. The median follow-up duration for all patients was 36.0 months. The OS rates for the 60 Gy and 70 Gy groups were 86.3% and 89.0%, respectively, with 3-year OS rates of 92.4% and 89.0% (P = 0.375). The 3-year DFS rates were 91.0% in the 60 Gy group and 81.0% in the 70 Gy group (P = 0.096), indicating no significant differences between the groups. The incidence of acute Grade 2 or higher urinary toxicities was comparable between the two groups (60 Gy group vs 70 Gy group: 9.6% vs 9.6%, P = 1.0), while the 70 Gy group demonstrated an advantage for late Grade 2 or higher toxicities (60 Gy group vs 70 Gy group: 12.3% vs 2.8%, P = .028). For the GI system, the incidence of acute toxicities was higher in the 60 Gy group, albeit not statistically significant (60 Gy group vs 70 Gy group: 11.0% vs 6.8%, P = .383), while late toxicities were equivalent between the groups (60 Gy group vs 70 Gy group: 1.4% vs 1.4%, P = 1.0).

Conclusion

Both MHRT fractionation patterns demonstrate comparable survival outcomes and toxicities in early-stage prostate cancer, suggesting MHRT’s viability as a primary treatment. The 60 Gy/20f pattern marginally favored survival, albeit not with statistical significance.

Keywords

prostate cancer moderate-hypofractionated propensity score matching radiation therapy dose fractionation patterns

Introduction

Prostate cancer is the second most prevalent cancer (after lung cancer) in men and the fourth most common overall.^1,2 In 2020, there were more than 1.4 million new cases of prostate cancer.² Currently, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for the treatment of localized prostate cancer primarily base their recommendations on a prognosis estimated through risk stratification.³ The main treatment options are radical prostatectomy (RP), radiotherapy, and androgen deprivation therapy (ADT). As one of the standard treatment choices, radiotherapy primarily comprises two types: brachytherapy (BT) and external beam radiotherapy (EBRT).⁴ Most patients undergo external beam radiation therapy.

Radiotherapy is divided into different fractionation patterns based on the single radiation dose. The conventional fractionation regimen consists of 1.8-2.0 Gy per fraction, whereas large fractionation is further subdivided into moderate-hypofractionated radiotherapy (MHRT) (2.4-3.4 Gy per fraction) and ultra-hypofractionated radiotherapy (UHRT) (≥5 Gy per fraction), according to the American Society for Radiation Oncology (ASTRO), American Society of Clinical Oncology (ASCO), and American Urological Association (AUA) hypofractionation guideline.⁵ The α/β ratio reflects the fraction size sensitivity of tumor, with a lower α/β ratio suggesting greater sensitivity.⁶ For most tumor tissues, the α/β ratio approximates 10 Gy, while for prostate cancer cells, characterized as late-responding tissues, the ratio is only about 1.5 Gy.^7-10 This suggests that large fractionation may improve the therapeutic ratio, particularly in relation to late gastrointestinal (GI) and genitourinary (GU) toxicities.¹¹ Additionally, larger single radiation dose entails fewer fractions, thus facilitating a faster and more cost-effective EBRT course, and enhancing patient compliance.¹² There have been studies demonstrated that MHRT in prostate cancer could achieve higher biochemical control rates.^11,13-15 However, studies comparing different dose fractionation patterns within MHRT in early-stage prostate cancer remain relatively limited.

In this study, we compared two different MHRT dose fractionation patterns, 60 Gy in 20 fractions (60 Gy/20f) and 70 Gy in 28 fractions (70 Gy/28f), among early-stage prostate cancer patients who did not undergo RP. We examined their clinical outcomes, survival benefits, and toxic side effects. Specifically, we performed a propensity score matching analysis¹⁶ to reduce bias in estimating treatment effects when analyzing non-random observational data.

Methods

Patients

This was a retrospective study. We reviewed all patients diagnosed with prostate cancer who received radiotherapy at Peking Union Medical College Hospital (PUMCH), China, from October 2014 to June 2023, totaling 860 cases. The median follow-up period for all patients was 28 months (range: 4-56 months). After excluding those who had undergone surgical local treatment or radiotherapy for metastatic prostate cancer lesions, 187 patients diagnosed with early-stage prostate cancer ultimately met the inclusion criteria: 101 in the 60 Gy group and 86 in the 70 Gy group. All enrolled patients underwent abdominal and pelvic imaging or prostate-specific membrane antigen positron emission tomography (PSMA-PET) scans to confirm the absence of local invasion of adjacent organs, local lymph node metastasis, and distant metastasis. After excluding an additional 25 patients lost to follow-up, 86 patients in the 60 Gy group and 76 in the 70 Gy group were included in the analysis. All patients were diagnosed with pathologically confirmed prostate cancer. Cancer staging utilized the TNM staging system of the American Joint Committee on Cancer (AJCC) and the prostate cancer grading score of the International Society of Urological Pathology (ISUP). Patients were classified as intermediate-risk or high-risk according to the D'Amico risk classification system.¹⁷ The administration of adjunctive ADT before and after radiotherapy was prescribed at the discretion of the attending urologist and recommended for patients at intermediate risk (6 months) and high risk (24-36 months).

The report of this study conforms to the STROBE guidelines.¹⁸ The study protocol was approved by the Ethics Committee of Peking Union Medical College Hospital (PUMCH), China (No. I-25PJ0280). The requirement for obtaining patient consent was waved by the IRB, and we have de-identified all patient details.

Treatment

All patients underwent radiotherapy using intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), or Tomotherapy (TOMO). For the 60 Gy group, patients primarily followed two treatment plans: the first encompassed the prostate and seminal vesicles within the clinical target volume (CTV) using a dose fractionation pattern of 60 Gy/20f (3 Gy/f); the second comprised CTV1 including the prostate and high-risk seminal vesicles for preventive propose with a dose fractionation pattern of 60 Gy/20f (3 Gy/f), and CTV2 including the low-risk seminal vesicles with a dose fractionation pattern of 52 Gy/20f (2.6 Gy/f). For the 70 Gy group, the CTV included the prostate and seminal vesicles, with a dose fractionation pattern of 70 Gy/28f (2.5 Gy/f). For the delineation of the seminal vesicle target volume, our center referred to the 2018 ESTRO ACROP guideline¹⁹: For low-risk patients, the seminal vesicles were not delineated. For intermediate-risk patients, the seminal vesicles within 1.4 cm of the prostate on the axial plane were delineated. For localized high-risk patients, the seminal vesicles within 2.2 cm of the prostate on the axial plane were delineated. The planning target volume (PTV) was defined by adding a 5 mm margin around the CTV to avoid the rectum. The principal organs at risk (OARs) included the bladder, rectum, small intestine, and bilateral femoral heads. The regimen and duration of adjunctive ADT before and after radiotherapy were prescribed at the discretion of the attending urologist, tailored to individual patient needs.

All patients underwent bowel preparation and maintained moderate bladder filling before each radiotherapy session. Daily cone beam computed tomography (CBCT) image guidance was performed before each fraction to confirm the target area. For each CBCT, the images were carefully registered with the reference images based on bone and soft tissue to minimize positioning errors. A physician performed quality control on all CBCT images weekly.

Outcomes

Biochemical failure followed the Phoenix definition, marked by a nadir plus a ≥2 ng/ml increase in prostate-specific antigen (PSA). Disease-free survival (DFS) was calculated from the end of radiotherapy to the date of biochemical failure, local recurrence, lymph node recurrence, or occurrence of distant metastasis, as diagnosed by imaging. The time from the end of treatment to the date of death from any cause or to the last contact date during follow-up was defined as overall survival (OS). In this retrospective study, the primary endpoints reported were OS and DFS. Follow-up was characterized as the period from the end of radiotherapy to the date of last contact. We systematically assessed toxicity and side effects based on the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 and v5.0 during follow-ups and through review of patient files, specifically targeting GI and GU toxicities. Acute toxicity was defined as that occurring from the start of radiotherapy to three months post-radiotherapy, while events more than three months post-treatment were categorized as late toxicity.

Statistical Analysis

Propensity score generation and 1:1 matching of patients were conducted between the 60 Gy and 70 Gy groups to minimize selection bias in treatment allocation. This process involved sampling without replacement, with the clamp value set to 0.05. Matching relied primarily based on the clinical and pathological baseline characteristics of the patients, including four covariates: age, PSA value at diagnosis, T stage, and ISUP grading. OS and DFS calculations were performed using Kaplan-Meier analysis. The log-rank test was utilized to evaluate differences in survival outcomes between the 60 Gy and 70 Gy groups. Continuous and categorical variables were analyzed between the two groups using the t-test and Fisher’s exact test, respectively. All statistical analyses were conducted in the R software environment for statistical computing and graphics (version 4.1). Statistical significance was established at P < .05 for all tests.

Results

A total of 162 patients were included in the study. The median follow-up period for all patients was 36.0 months (range: 4-114), with the 60 Gy group at 40.0 months (range: 8-114) and the 70 Gy group at 31.5 months (range: 4-80). Based on covariates such as age, PSA value at diagnosis, T stage, and ISUP grading, 73 patients in the 60 Gy group and 73 in the 70 Gy group were successfully matched. The baseline conditions, clinical data, laboratory tests, and initial staging were considered balanced between the two groups, as detailed in Table 1. After PSM, the total prostate volumes in the two groups were 46.7 ± 7.1 mL and 46.3 ± 5.1 mL, respectively (P = .69).

Table 1.

Baseline Characteristics for Patients in 60 Gy and 70 Gy Groups Before and After Matching.

	Before PSM (n = 162)			After PSM (n = 146)
Characteristics	60 Gy (n = 86)	70 Gy (n = 76)	P-value	60 Gy (n = 73)	70 Gy (n = 73)	P-value
Age (y), mean ± SD	74.79 ± 7.18	73.78 ± 8.85	.127	74.52 ± 6.74	74.11 ± 8.05	.739
PSA at diagnosis, mean ± SD	36.44 ± 53.55	28.14 ± 30.09	.188	25.07 ± 27.61	28.85 ± 30.49	.433
T-stage, n (%)			.278			.348
T1	11 (12.8%)	8 (10.5%)		9 (12.3%)	8 (11.0%)
T2	63 (73.3%)	50 (65.8%)		53 (72.6%)	47 (64.4%)
T3	12 (14.0%)	18 (23.7%)		11 (15.1%)	18 (24.7%)
Pathological ISUP grading, n (%)			.434			.487
1	12 (14.0%)	13 (17.1%)		12 (16.4%)	11 (15.1%)
2	17 (19.8%)	21 (27.6%)		16 (21.9%)	21 (28.8%)
3	14 (16.3%)	6 (7.9%)		13 (17.8%)	6 (8.2%)
4	21 (24.4%)	19 (25.0%)		17 (23.3%)	19 (26.0%)
5	22 (25.6%)	17 (22.4%)		15 (20.5%)	16 (21.9%)

Abbreviations: ISUP, International Society of Urological Pathology; PSA, prostate-specific antigen; PSM, propensity score matching; SD, standard deviation; y: year.

The efficacy comparison between the 60 Gy and 70 Gy groups post-matching is summarized in Table 2. By the end of the last follow-up of the study, the OS for the 60 Gy group was 86.3%, vs 89.0% for the 70 Gy group. Furthermore, the 3-year OS stood at 92.4% for the 60 Gy group, compared to 89.0% for the 70 Gy group (P = .375). The 3-year DFS reached 91.0% in the 60 Gy group and 81.0% in the 70 Gy group (P = .096). The two recurrences in the 60 Gy group were distant metastases in the right ureter and lung, with the metastasis times for these two patients being 35 months and 27 months after radiotherapy, respectively. The six recurrences in the 70 Gy group included two biochemical recurrences, two local recurrences, one bone metastasis, and one recurrence near the intra- and extra-iliac vessels’ lymph nodes. The average time to biochemical recurrence was 6.5 months, to local recurrence was 33 months, and to distant metastasis (lymph node and bone) was 32 and 24 months, respectively. Kaplan-Meier curves for OS and DFS, stratified by dose fractionation patterns, are depicted in Figure 1A and B. Furthermore, there were 26 and 28 intermediate-risk patients in the 60 Gy and 70 Gy groups, respectively, and 47 and 45 high-risk patients, respectively. The survival curves (Figure 1C and D) show the differences between the two treatment groups in intermediate- and high-risk patients. In the intermediate-risk group, the 60 Gy group showed a trend toward longer survival, but the difference was not significant (P = .071), while in the high-risk group, there was no significant survival difference between the two groups (P = .229).

Table 2.

Efficacy Comparison Between the 60 Gy Group and the 70 Gy Group After Matching.

Outcomes	60 Gy (n = 73)		70 Gy (n = 73)
Death from any cause	10 (13.7%)		8 (11.0%)
Death from tumor	2 (2.7%)		4 (5.5%)
OS (%)	1yr-OS	100.0%	1yr-OS	98.3%
	3yr-OS	92.4%	3yr-OS	89.0%
	5yr-OS	80.4%	5yr-OS	82.0%
DFS (%)	1yr-DFS	100.0%	1yr-DFS	95.5%
	3yr-DFS	91.0%	3yr-DFS	81.0%
	5yr-DFS	82.4%	5yr-DFS	74.1%

Abbreviations: DFS, disease-free survival; OS, overall survival; yr, year.

Figure 1.

Kaplan-Meier Survival Curves for Patients. (A) Difference in Overall Survival Between the 60 Gy and 70 Gy Groups. (B) Difference in Disease-Free Survival Between the 60 Gy and 70 Gy Groups. (C) Difference in Overall Survival Between the 60 Gy and 70 Gy Groups in the Intermediate-Risk Patient Subgroup. (D) Difference in Overall Survival Between the 60 Gy and 70 Gy Groups in the High-Risk Patient Subgroup.

In both groups, 3 patients in each group did not receive adjuvant or neoadjuvant ADT treatment due to comorbidities or compliance issues. The average duration of continued post-radiotherapy endocrine therapy amounted to 31.7 ± 27.1 months for the 60 Gy group and 23.2 ± 19.7 months for the 70 Gy group. One patient received additional local radiotherapy following local recurrence, whereas all other patients underwent no further treatments beyond endocrine therapy after radiotherapy.

Side events occurred within three months after the end of radiotherapy were designated as acute toxicities, otherwise late toxicities. Among all patients, urinary toxicity was the most prevalent, followed by GI toxicity. A small number of patients experienced acute bone marrow suppression, while very few reported late bone-related radiotherapy side effects. The specific incidence rates of urinary and GI events are detailed in Figure 2.

Figure 2.

Clinical Manifestations of Toxicities in the Urinary and GI Systems. A1: Urinary Toxicities in the 60 Gy Group; A2: Urinary Toxicities in the 70 Gy Group; B1: GI Toxicities in the 60 Gy Group; B2: GI Toxicities in the 70 Gy group. GI: gastrointestinal.

In the 60 Gy group, the occurrence of Grade 2 or higher urinary acute and late toxicities was 9.6% and 12.3%, respectively, while in the 70 Gy group, it was 9.6% and 2.8%, respectively. The incidence of acute Grade 2 or higher urinary toxicities was comparable between the two groups (60 Gy group vs 70 Gy group: 9.6% vs 9.6%, P = 1.0). However, regarding late Grade 2 or higher toxicities, the 70 Gy group demonstrated a significant advantage (60 Gy group vs 70 Gy group: 12.3% vs 2.8%, P = .028).

For the GI system, the primary acute toxicity included diarrhea and rectal bleeding, whereas the predominant late toxicity was rectal bleeding. In the 60 Gy group, the occurrence of Grade 2 or higher GI acute and late toxicities was 11.0% and 1.4%, respectively, while in the 70 Gy group, it was 6.8% and 1.4%, respectively. Between the 60 Gy and 70 Gy groups, the incidence of acute toxicities was higher in the 60 Gy group, although not statistically significant (60 Gy group vs 70 Gy group: 11.0% vs 6.8%, P = .383). The incidence of late toxicities was identical between the two groups (60 Gy group vs 70 Gy group: 1.4% vs 1.4%, P = 1.0).

Regarding other side effects, one patient in the 60 Gy group and three patients in the 70 Gy group experienced mild bone marrow suppression during radiotherapy. Additionally, two patients in each group experienced non-metastatic bone-related side effects, manifesting as pain in the hip and iliac bone areas, which included one case of intertrochanteric femur fracture after radiotherapy. Moreover, one patient in each group reported significant declines in sexual function following treatment. The corresponding toxicities for each system are detailed in Table 3.

Table 3.

Comparison of Toxicities in Urinary and Gastrointestinal Systems Between 60 Gy and 70 Gy Groups.

	60 Gy (n = 73)		70 Gy (n = 73)
Toxicities	Acute toxicity	Late toxicity	Acute toxicity	Late toxicity
Urinary system	27 (37.0%)	35 (34.2%)	31 (42.5%)	22 (30.1%)
Grade 1	20 (27.4%)	16 (21.9%)	24 (32.9%)	20 (27.4%)
Grade 2	6 (8.2%)	7 (9.6%)	5 (6.8%)	1 (1.4%)
≥ Grade 3	1 (1.4%)	2 (2.7%)	2 (2.7%)	1 (1.4%)
GI system	32 (43.8%)	3 (4.1%)	18 (24.7%)	2 (2.7%)
Grade 1	24 (32.9%)	2 (2.7%)	13 (17.8%)	1 (1.4%)
Grade 2	4 (5.5%)	1 (1.4%)	4 (5.5%)	1 (1.4%)
≥ Grade 3	4 (5.5%)	0	1 (1.4%)	0

Abbreviations: GI: gastrointestinal.

Regarding dose limitations for OARs in radiotherapy, assuming an α/β ratio of 2 for normal tissue, the average biologically equivalent dose (BED) for 50% of the rectum dose in the 70 Gy and 60 Gy groups was 19.9 ± 8.7 Gy and 21.2 ± 11.7 Gy respectively, showing no significant difference (P = .17). The average BED for 50% of the bladder dose was 19.0 ± 18.0 and 22.4 ± 16.0 Gy respectively for 70 Gy and 60 Gy (P = .36). Detailed information is provided in Figure 3.

Figure 3.

Comparison of BED for Organs at Risk Between the 70 Gy and 60 Gy Groups. From Left to Right: *V_50% Rectum, **V_50% Bladder. BED: Biologically Equivalent Doses.

Discussion

In EBRT for prostate cancer, owing to its low sensitivity to conventionally fractionated radiotherapy (CFRT), the standard fractionation dose is set at 1.8-2 Gy, aiming for a total dose range of 70-81 Gy.²⁰ The introduction of MHRT has shed new light on this scenario. Several clinical studies have substantiated the efficacy and safety of MHRT in treating prostate cancer, as demonstrated in Table 4. The study by Lee et al²¹ encompassed 1115 low-risk prostate cancer patients, who were randomly allocated in a 1:1 ratio to either the CFRT (73.8 Gy/41f) or MHRT (70 Gy/28f) groups. The results indicated that the 5-year DFS rate for the MHRT group was 86.3%, comparable to the 85.3% observed in the CFRT group. However, patients treated with MHRT experienced an increase in late Grade 2 and 3 GI and GU adverse events. In the randomized, non-inferiority Phase 3 CHHiP trial,¹¹ 3216 patients with localized prostate cancer were recruited and randomly assigned to CFRT (74 Gy/37f) or one of two large fractionation patterns (60 Gy/20f or 57 Gy/19f), with a median follow-up time of 62.4 months. The 5-year rates of biochemical or clinical failure (BCF) for the three groups were 88.3%, 90.6%, and 85.9%, respectively. The study results indicated that the 60 Gy/20f MHRT pattern was not inferior to the 74 Gy/37f CFRT pattern, and there was no significant difference in the proportion or cumulative incidence of side effects after 5 years. Datta et al²² conducted a systematic review and meta-analysis of 10 trials from 9 studies involving 8146 patients. The findings showed that MHRT provides treatment outcomes similar to CFRT in localized or locally advanced prostate cancer, but with a significantly higher risk of acute GI toxicity. Currently, the NCCN guidelines recommend radiotherapy options for prostate cancer that include 60 Gy/20f, 70.2 Gy/26f, and 70 Gy/28f.²³

Table 4.

Completed Studies on Moderate-Hypofractionated Radiotherapy (MHRT) in Prostate Cancer.

Study	Patients	Condition	Study design	Results
Arcangeli et al, 2010²⁴	168	High-risk PCa	MHRT: 62 Gy/20f vs CFRT: 80 Gy/40f	3-year FFBF: 87% vs 79%; 3-year Grade 2 late GI and GU rates: 17% vs 16%, 14% vs 11%. No difference was found for late toxicity.
Pollack et al, 2013²⁵	303	PCa	MHRT: 70.2 Gy/26f vs CFRT: 76 Gy/38f	5-year BCDF: 23.3% vs 21.4%; There were no statistically significant differences in late toxicity.
Aluwini et al, 2015²⁶	820	Intermediate-risk to high-risk PCa	MHRT: 64.6 Gy/19f vs CFRT: 78 Gy/39f	Acute ≥ Grade 2 GI AEs: 13% vs 13%; Acute ≥ Grade 2 GU AEs: 23% vs 22%.
Incrocci et al, 2016²⁷	820	Intermediate-risk to high-risk localized PCa	MHRT: 64.6 Gy/19f vs CFRT: 78 Gy/39f	5-year relapse-free survival: 80.5% vs 77.1%; Cumulative incidence of acute Grade 2 or worse GI AEs was significantly higher after MHRT; 3-year cumulative incidence of late GI and GU Grade 2 or worse AEs was comparable.
Lee et al, 2016²¹	1115	Low-risk PCa	MHRT: 70 Gy/28f vs CFRT: 73.8 Gy/41f	5-year DFS: 86.3% vs 85.3%; Late Grade 2 and 3 GI and GU AEs increased in MHRT.
Dearnaley et al, 2016¹¹	3216	Localized PCa	MHRT: 60 Gy/20f vs MHRT: 57 Gy/19f vs CFRT: 74 Gy/37f	5-year BCFF: 90.6% vs 85.9% vs 88.3%; There were no significant differences in either the proportion or cumulative incidence of 5-year AEs.
Catton et al, 2017²⁸	1206	Intermediate-risk PCa	MHRT: 60 Gy/20f vs CFRT: 78 Gy/39f	5-year BCFF: 85% vs 85%; No significant differences were detected for ≥ Grade 3 late GI and GU toxicity.
Hoffman et al, 2018²⁹	206	Localized PCa	MHRT: 72 Gy/30f vs CFRT: 75.6 Gy/42f	8-year failure rate: 10.7% vs 15.4%; There was no difference in OS; There was a nonsignificant increase in late Grade 2/3 GI and GU toxicity with MHRT.
Brand et al, 2019¹⁵	874	Low-risk to intermediate-risk localized PCa	MHRT/CFRT: 62 Gy/20f or 78 Gy/39f vs SBRT: 36•25 Gy/5f	Acute ≥ Grade 2 GI AEs: 12% vs 10%; Acute ≥ Grade 2 GU AEs: 27% vs 23%.
Bruner et al, 2019³⁰	1092	Low-risk PCa	MHRT: 70 Gy/28f vs CFRT: 73.8 Gy/41f	Treatment with MHRT is noninferior to CFRT in terms of DFS and in PCa-specific and general QOL.
Vries et al, 2020³¹	820	Intermediate-risk to high-risk PCa	MHRT: 64.6 Gy/19f vs CFRT: 78 Gy/39f	7-year relapse-free survival: 71.7% vs 67.6%; OS: 80.8% vs 77.6%.
Tamihardja et al, 2021¹³	346	Localized PCa	MHRT: 73.9 Gy/32f vs 76.2 Gy/33f	5-year FFBF: 85.4%; 5-year PSS: 94.8%; 5-year and 10-year OS: 83.8% and 66.3%; 5-year and 10-year freedom from distant metastasis rates: 92.2% and 88%; Cumulative 5-year late Grade 3 GU and GI toxicity: 4.0% and 1.2%.
Syndikus et al, 2023³²	3216	Localized PCa	MHRT: 60 Gy/20f vs MHRT: 57 Gy/19f vs CFRT: 74 Gy/37f	10-year BCFF: 79.8% vs 73.4% vs 76.0%; 10-year OS: 82.9% vs 79.9% vs 78.5%; Late co-morbidities were very low across all groups.

Abbreviations: AEs, adverse events; BCDF, biochemical and/or clinical disease failure; BCFF, biochemical or clinical failure free; CFRT, conventionally fractionated radiotherapy; DFS, disease-free survival; FFBF, freedom from biochemical failure; GI, gastrointestinal; GU, genitourinary; MHRT, moderate-hypofractionated radiotherapy; OS, overall survival; PCa, prostate cancer; PSS, prostate cancer-specific survival; QOL, quality of life; SBRT, stereotactic body radiotherapy; xGy/nf, x Gy in n fractions.

However, studies that compare different dose fractionation patterns in MHRT are relatively scarce. In this study, we compared two distinct MHRT dose fractionation patterns, 60 Gy/20f and 70 Gy/28f, among early-stage prostate cancer patients who had not undergone surgery and were undergoing radical radiotherapy. This methodology is relatively novel compared to other studies. Furthermore, we conducted a propensity score matching analysis to mitigate potential biases in the efficacy evaluation, thereby enhancing the reliability of the results.

This study encompassed 162 early-stage prostate cancer patients, and following propensity score matching, each of the 60 Gy and 70 Gy groups included 73 patients. The median follow-up duration for all patients was 36.0 months. From the results, the 60 Gy group shows a slight survival advantage compared to the 70 Gy group, but there is no significant statistical difference in OS and DFS. Regarding side effects, the incidence of grade 2 or higher acute urinary toxicities was similar between the two groups. However, the 70 Gy group exhibited significantly fewer late urinary toxicities, especially concerning long-term side effects such as urinary frequency and urgency. In terms of GI toxicities, the 60 Gy group experienced more noticeable acute GI toxicities, including constipation and diarrhea. Grade 2 or higher late GI toxicities were limited in both groups, and no significant difference was observed between the groups. Overall, apart from late Grade 2 or higher urinary system toxicity where the 70 Gy group held an advantage, there were no significant statistical differences in efficacy and overall urinary and GI system toxicity between the groups.

Regrettably, MHRT has not yet achieved widespread adoption in prostate cancer radiotherapy. Although many studies have demonstrated that MHRT is safe and effective for localized prostate cancer, its efficacy is not significantly superior to that of CFRT, and it may lead to an increase in early adverse reactions.^22,33 Furthermore, owing to substantial inter-fraction errors and the steep dose-volume relationship of late toxicity post-treatment, MHRT necessitates advanced radiotherapy technologies and precise image-guidance capabilities.^11,34 Nonetheless, MHRT continues to represent a significant future trend in prostate cancer radiotherapy. Compared to CFRT, MHRT utilizes higher single doses, potentially reducing treatment time by 1-2 weeks. Shorter treatment durations entail more efficient courses of treatment and can enhance patient compliance.¹² Higher single doses also elevate the therapeutic gain ratio, which benefits the enhancement of killing power against tumor cells.¹¹

Due to the numerous advantages of large fraction radiotherapy over CFRT, UHRT has increasing come into focus and commenced usage in clinical trials concerning prostate cancer radiotherapy. In 2019, Marvaso et al³⁵ involved 421 patients with localized prostate cancer and, after conducting a propensity score matching analysis, compared the efficacy and post-treatment toxicity between UHRT (32.5-35 Gy/5f) and MHRT (70.2 Gy/26f). The study results demonstrated that, compared to MHRT, UHRT presented reduced risks of both acute and late toxicity while providing comparable oncological outcomes. Widmark et al¹⁴ conducted a randomized, non-inferiority Phase 3 trial, HYPO-RT-PC, enrolling 1200 patients with intermediate to high-risk prostate cancer who were randomly assigned to UHRT (42.7 Gy/7f) and CFRT (78 Gy/39f) groups. The results indicated that for intermediate to high-risk prostate cancer, UHRT’s survival without failure was not inferior to that of CFRT, though early side effects were more pronounced. Late toxicity was comparable between the two treatment groups. It is noteworthy that only one patient in each group reported significant sexual dysfunction, which seems to contradict the application of ADT in these patients. This may be due to the already weak baseline sexual function of these elderly patients or their potential to conceal the situation for privacy reasons. Currently, numerous clinical trials investigating prostate cancer UHRT are ongoing. The optimal radiotherapy fractionation regimen for radical prostate radiotherapy, whether it should be UHRT, MHRT, or CFRT, and whether personalized fractionation schemes are recommended for different patients, requires further investigation.

Additionally, most patients in our cohort were in the high-risk group. Stratified survival analysis showed that MHRT seemed to have an advantage in the intermediate-risk group, whereas there was no significant difference in overall survival in the high-risk group. The POP-RT trial,³⁶ a phase III, single-center, randomized controlled trial comparing survival differences between high-risk prostate cancer patients, found that whole pelvic radiotherapy provided better DFS and biochemical failure-free survival (BFFS) compared to prostate-only radiotherapy. However, there was no significant difference in OS. These findings suggest that for high-risk patients, it may not be enough to explore different dose fractionation schemes alone. Further research is needed to optimize target volume irradiation, and potentially even explore the joint optimization of fractionation schemes and target volumes, to achieve additional survival benefits.

Despite employing propensity score matching analysis, this study, being non-prospective and single-center, still exhibits inherent flaws, including a limited patient cohort, short follow-up time and biases that are challenging to control or eradicate. Moving forward, it would be prudent to design a prospective, randomized controlled trial (RCT) to more thoroughly compare and analyze the differences in efficacy and post-treatment toxicity between the two MHRT dose fractionation patterns.

Conclusions

Our study demonstrates that among early-stage prostate cancer patients who have not undergone surgery and are receiving radical radiotherapy, the two MHRT dose fractionation patterns, 60 Gy/20f and 70 Gy/28f, yield comparable survival and oncological outcomes with no significant statistical differences. In terms of safety, aside from the 70 Gy group displaying an advantage in late Grade 2 or higher urinary system toxicity, there were no significant differences in overall acute or late urinary and GI toxicities between the two groups. This further substantiates the efficacy and safety of MHRT in early-stage prostate cancer patients undergoing radical radiotherapy, underscoring MHRT’s potential as a primary treatment modality for prostate cancer in the future.

Footnotes

Acknowledgements

We would like to extend our gratitude to all our colleagues for their support.

ORCID iD

Zhikai Liu

Statements and Declarations

Author Contributions

Y.T. and W.C. contributed equally to this manuscript.

Y.T. and W.C. were responsible for the conceptualization of the study, study design, data analysis and wrote the manuscript draft.

H.Z., J.S., H.G., X.H., K.H., F.Z. and Z.L. were responsible for the data collection and curation.

Z.L. contributed to the design and supervision of the study.

All authors read and approved the final manuscript.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by National Key R&D Program of China, Ministry of Science and Technology of the People’s Republic of China. (Grant No. 2022YFC2407100, 2022YFC2407102).

Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.*

Appendix

References

Rawla

. Epidemiology of prostate cancer. Prostate cancer; epidemiology; incidence; mortality; trends; survival; etiology; risk factors; prevention. World J Oncol. 2019;10(2):63-89.

Prostate cancer statistics . World cancer research fund international. https://www.wcrf.org/cancer-trends/prostate-cancer-statistics/. Accessed 4 May 2024.

Schaeffer

Srinivas

Adra

, et al. Prostate cancer, version 3.2024: featured updates to the NCCN guidelines %J. J Natl Compr Cancer Netw. 2024;22(3):140-150.

Ito

Sasamura

Takase

, et al. Comparison of physician-recorded toxicities and patient-reported outcomes of five different radiotherapy methods for. Prostate Cancer. 2021;41(5):2523-2531.

Morgan

Hoffman

Loblaw

, et al. Hypofractionated radiation therapy for localized prostate cancer: executive summary of an ASTRO, ASCO, and AUA evidence-based guideline. Pract Radiat Oncol. 2018;8(6):354-360.

Fowler

. The radiobiology of prostate cancer including new aspects of fractionated radiotherapy. Acta Oncol. 2005;44(3):265-276.

Brenner

Hall

. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys. 1999;43(5):1095-1101.

Miralbell

Roberts

Zubizarreta

Hendry

. Dose-fractionation sensitivity of prostate cancer deduced from radiotherapy outcomes of 5,969 patients in seven international institutional datasets: α/β = 1.4 (0.9-2.2) Gy. Int J Radiat Oncol Biol Phys. 2012;82(1):e17-e24.

Fowler

Toma-Dasu

Dasu

. Is the α/β ratio for prostate tumours really low and does it vary with the level of risk at diagnosis? Anticancer Res. 2013;33(3):1009-1011.

10.

Daşu

. Is the alpha/beta value for prostate tumours low enough to be safely used in clinical trials? Clin Oncol (R Coll Radiol). 2007;19(5):289-301.

11.

Dearnaley

Syndikus

Mossop

, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 2016;17(8):1047-1060.

12.

Zemplényi

Kaló

Kovács

, et al. Cost-effectiveness analysis of intensity-modulated radiation therapy with normal and hypofractionated schemes for the treatment of localised prostate cancer. Eur J Cancer Care (Engl). 2018;27(1):e12430.

13.

Tamihardja

Schortmann

Lawrenz

, et al. Moderately hypofractionated radiotherapy for localized prostate cancer: updated long-term outcome and toxicity analysis. Strahlenther Onkol. 2021;197(2):124-132.

14.

Widmark

Gunnlaugsson

Beckman

, et al. Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial. Lancet. 2019;394(10196):385-395.

15.

Brand

Tree

Ostler

, et al. Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial. Lancet Oncol. 2019;20(11):1531-1543.

16.

Haukoos

Lewis

. The propensity score. JAMA. 2015;314(15):1637-1638.

17.

D'Amico

Whittington

Malkowicz

, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280(11):969-974.

18.

von Elm

Altman

Egger

Pocock

Gøtzsche

Vandenbroucke

. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med. 2007;147(8):573-577.

19.

Salembier

Villeirs

De Bari

, et al. ESTRO ACROP consensus guideline on CT- and MRI-based target volume delineation for primary radiation therapy of localized prostate cancer. Radiother Oncol. 2018;127(1):49-61.

20.

Swisher-McClure

Mitra

Woo

Smaldone

Uzzo

Bekelman

. Increasing use of dose-escalated external beam radiation therapy for men with nonmetastatic prostate cancer. Int J Radiat Oncol Biol Phys. 2014;89(1):103-112.

21.

Lee

Dignam

Amin

, et al. Randomized phase III noninferiority study comparing two radiotherapy fractionation schedules in patients with low-risk prostate cancer. J Clin Oncol. 2016;34(20):2325-2332.

22.

Datta

Stutz

Rogers

Bodis

. Conventional versus hypofractionated radiation therapy for localized or locally advanced prostate cancer: a systematic review and meta-analysis along with therapeutic implications. Int J Radiat Oncol Biol Phys. 2017;99(3):573-589.

23.

Schaeffer

Srinivas

Adra

, et al. Prostate cancer, version 4.2023, NCCN clinical Practice guidelines in Oncology. J Natl Compr Canc Netw. 2023;21(10):1067-1096.

24.

Arcangeli

Saracino

Gomellini

, et al. A prospective phase III randomized trial of hypofractionation versus conventional fractionation in patients with high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2010;78(1):11-18.

25.

Pollack

Walker

Horwitz

, et al. Randomized trial of hypofractionated external-beam radiotherapy for prostate cancer. J Clin Oncol. 2013;31(31):3860-3868.

26.

Aluwini

Pos

Schimmel

, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): acute toxicity results from a randomised non-inferiority phase 3 trial. Lancet Oncol. 2015;16(3):274-283.

27.

Incrocci

Wortel

Alemayehu

, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016;17(8):1061-1069.

28.

Catton

Lukka

C-S

, et al. Randomized trial of a hypofractionated radiation regimen for the treatment of localized prostate cancer. J Clin Oncol. 2017;35(17):1884-1890.

29.

Hoffman

Voong

Levy

, et al. Randomized trial of hypofractionated, dose-escalated, intensity-modulated radiation therapy (IMRT) versus conventionally fractionated IMRT for localized prostate cancer. J Clin Oncol. 2018;36(29):2943-2949.

30.

Bruner

Pugh

Lee

, et al. Quality of life in patients with low-risk prostate cancer treated with hypofractionated vs conventional radiotherapy: a phase 3 randomized clinical trial. JAMA Oncol. 2019;5(5):664-670.

31.

de Vries

Wortel

Oomen-de Hoop

Heemsbergen

Pos

Incrocci

. Hyprofractionated versus conventionally fractionated radiation therapy for patients with intermediate- or high-risk, localized, prostate cancer: 7-year outcomes from the randomized, multicenter, open-label, phase 3 HYPRO trial. Int J Radiat Oncol Biol Phys. 2020;106(1):108-115.

32.

Syndikus

Griffin

Philipps

, et al. 10-Year efficacy and co-morbidity outcomes of a phase III randomised trial of conventional vs. hypofractionated high dose intensity modulated radiotherapy for prostate cancer (CHHiP; CRUK/06/016). J Clin Oncol. 2023;41(6_suppl):304.

33.

Lilleby

Meidahl Petersen

Daugaard

Anne Perell

. Current evidence for moderate and ultra-hypofractionated radiation therapy in prostate cancer: a summary of the results from phase 3 randomised trials. Scand J Urol. 2023;58:21-27.

34.

South

Khoo

Naismith

Norman

Dearnaley

. A comparison of treatment planning techniques used in two randomised UK external beam radiotherapy trials for localised prostate cancer. Clin Oncol (R Coll Radiol). 2008;20(1):15-21.

35.

Marvaso

Ciardo

Gandini

, et al. Comparison of outcomes and toxicity between extreme and moderate radiation therapy hypofractionation in localized prostate cancer: a propensity score analysis. Int J Radiat Oncol Biol Phys. 2019;105(4):735-744.

36.

Murthy

Maitre

Kannan

, et al. Prostate-only versus whole-pelvic radiation therapy in high-risk and very high-risk prostate cancer (POP-RT): outcomes from phase III randomized controlled trial. J Clin Oncol. 2021;39(11):1234-1242.